Bis-carbamic acid ester compounds, and a process of making same



2,789,981 Patented 23, 1957 United States Patent ice stable in aqueous solution so that they can be heat sterilised and kept in aqueous solution without impairing their eflicacy. For their practical application this is a point of significant value. i

5 Compounds derived from 3-oxypyridine by the method of the present invention, such ascompounds of the general formula on, 7 on,

BIS-CARBAMIC ACID ESTER COMPOUNDS, AND. A PROCESS OF MAKING SAME OttoSchmid, Bounding, near Linz, Austria, assignor. to Oesterreichische- Stickstoflwerke Aktiengesellschaft, Linz (Donau), Austria, an Austrian joint stock company No Drawing. Application'S'eptember 19, 1955,

Serial No. 535,289- 10 Claims priority, applicafion Austria September, 1954' exhibit similar properties.

17 Claims. (Cl. 260-92955) Acompoundunaccordance with the present invention This invention relates to a methodof preparing new and having the formula QH,)=.N.GH2.0H20.0C.N.( H1).N.O 0,:0.'CH2-OH5|.N;(CH3 3 [I OH; CH: 1 (21) has been observed to have a strong neuro-muscular eflfect.

For the preparation of thevcompoundsnobtained by substitution at the nitrogen atom of carbamic acid, and having the above-written general formulas, into the carboxy groups of dicarbamic acids of the general formula bis-carbamic acid esters.

It is known that certain synthesized carbamic acid esters of aromatic and heterocyclic oxy-comp'ounds' containing a quaternary nitrogen atom, such asderive, for instance, from m-dimethylaminophenol -or- 3-oxypyridine, are powerful choline-esteraseinhibitors and may be used medically in place of the natural'alkaloideserine. 25

It has now been ascertained, in accordance with the present invention that hitherto unknown compounds of the following general formulae similar tertiary or quaternary groups Z or RZX'conta-ining nitrogenand substituted in the'manner hereinbefore described are introduced, and the d-i-tertiary'compounds A A thus obtained maybe converted-into quaternary comor pounds.

RZ O Co- N B N O'O;Q .ZR H In order to carry out the synthesis, di-ca-rbamic acid I: A A :l di-chlorides of the generalxformula (wherein A is a lower alkylradical with 1 to 3, car-bon- F' I atoms, such as a methyl, ethyl, allyl, group, B apolymethylene Chain With Preferably 2 110 10 CH2 g PeZ a are reacted, if desired in the presence of acid-binding group cmltaining a tertiary nitmgen atom, Such as all substances, with oxy-compounds having; a" tertiary nitro- N, N.di-substituted B-aminoethyl group, an N.N.d.i-sub.- 40 gen atom, of the generalformula stituted 0-, mor p-aminophenyl group or a pyridine ZOH group, R a saturated or unsaturated, lower. aliphatic hydrocarbon group such as methyl, ethyl, propyl, allyl, preferably inthe form of their salts; The resultant dior alternatively a cyclohexyl, benzyl, or phenyl group, tertiary compounds canbe convertedinto theequivalent and X an anionic radical. such as I, Br, Cl, 01 quaternary compounds with the aid of compounds of the general formula RX.

T This result can also beobtained by reacting the diare 3150 y. 911011116. esfel'ase mhlbltcfscarbamic acid di-chl'orides. with (my-compounds contain- The Pharmacologlcal P p w O these new cQminga quaternary nitrogen-atom, ofithe general formula pounds differ in various respects from the substances that have. been .medically used in the past For instance, [RZ'OH] a compound prepared in accordance with the present in- In this instance, acid-'binding substances; may also be vention and having the formula added.

I CH3 CH3 7 (CHs)aIN NzfCiHs): has a stronger and more enduringeffect than-the bromemethylate of the dimethyl carbamic acid m-dimethylwould be substances of the following general formulae:

aminophenyl ester (neostigmin) although its toxicity is (RQMEQHLCHEQE less. Moreover, the undesirable effects (reminiscent of muscarine) exhibited by neestigmin and other compounds I,

(efiect on the intestinal motor system, salivation, activity (mm-Q of the heart, and so forth) are much reduced. The DH compounds formed, according to the-present inventiomby alkylation of the nitrogen atom of carbamic acid are.

Suitable oxy-compounds \vi th'a tertiary nitrogen atom (wherein R represents similar or different groups of the kind hereinbefore specified).

If the reaction is carried out directly with oxy-compounds having a quaternary nitrogen atom, ammonia compounds are used which can be derived from the said tertiary oxy-compounds and have the following formulae:

An advantageous method of performing the synthesis makes use of the di-tertiary bases which can be readily prepared. The alkyl group may be removed and a good yield of the required di-carbamic acid di-chloride obtained with the aid of phosgene as follows:

Y.N.B.N.Y CIOC.N.B.N.COC1

it A

In these formulae Y represents a low alkyl group, A is a lower alkyl group with 1w 3 carbon atoms, such as a methyl or ethyl group and B a polymethylene chain including preferably 2 to CH2 groups.

The reaction between the N.N-di-substituted di-carbamic acid di-chlorides of the specified constitution and oxy-compounds containing a tertiary or a quaternary nitrogen atom is preferably carried out in the presence of neutral solvents, such as for instance toluene or xylene. However, their presence is not a necessity. It is often an advantage to carry out the reaction in the presence of acid-binding substances such as for example tertiary amines. Especially good results can be achieved by using the alkali compounds of the oxy-compounds with a tertiary nitrogen atom that are to be employed for the reaction, such as for instance the sodium salts of mdimethylaminophenol or of B-oxypyridine or the like.

The quaternisation of the di-tertiary bases di-substituted at the carbamic acid nitrogen in accordance with the present invention and having the general formula surprisingly calls for the use of only low temperatures, the reaction generally taking place at room temperature, so that the usually undesirable effects of having to work at higher temperatures are not experienced and the reaction yields very pure products. Quaternisation is preferably also carried out in neutral solvents such as acetone, methyl ethyl ketone, methanol, ethanol, or in mixtures of solvents of this kind.

The invention will be illustrated by the following examples, in which the parts referred to are parts by weight.

Example 1 parts of N.N.N'.N'-tetramethylhexamethylene-diamine are added dropwise to 100 parts of a solution of 40% phosgene in toluene, the solution being continuously agitated. The phosgene which escapes through an ascending cooling tube together with the evolved methyl chloride is condensed in a cold trap. As soon as immixture has been completed, the temperature is raised to 100 C. and the phosgene recovered in the trap is vaporised and bubbled through the solution again, the escaping gas being recondensed and returned once more. The repeated passage through the reagents of the phosgene that has not yet reacted is continued for 7 hours. When the solution is cool it is passed through a filter, the remaining phosgene is removed from the clear solution by distillation and the remainder distilled in vacuo. The hexamethylene-bis-(N-methyl carbamic acid chloride) comes over at a pressure of 0.2 m./m. Hg at 169 to 170 C. in the form of a limpid rather viscous oil which soon crystallises completely. The yield is 10.6 parts.

A solution of 11.9 parts of m-dimethylaminophenol in 90 parts of xylene (isomer mixture) is added to a solu: tion of sodium methylate consisting of 2.0 parts of Na and 25 parts of methanol. The methanol is then completely removed by distillation and the temperature raised until the boiling point of the Xylene is reached. 9.9 parts of hexamethylene-bis-(N-methyl carbamic chloride) are added to the remainder which contains the sodium salt of m-dimethylaminophenol in the form of solid crystals. The reagent mixture is heated and maintained at a temperature of 100 C. andcontinuously agitated. After having been cooled it is washed three times in water, three times in a 5% solution of caustic soda, and another three times in water. The xylene is then evaporated in vacuo and the oily residue freed of any remaining traces of xylene by allowing it to stand in air when the product crystallised completely. In this manner 15.6 parts of hexamethylene-bis-(N-methyl carbamic acid m-dimethylaminophenylester) are obtained. After re-crystallisation in methanol or acetone petroleum ether, the substance which had been slightly coloured before, reappears in the form of a white, finely crystalline powder with a micro melting point between 88.5 and 90 C.

33.4 parts of hexamethylene-bis-(N-methyl carbamic acid m-dimethylaminophenylester) are dissolved in 85 parts of methyl ethyl ketone, and 100 parts of absolute ethanol and parts of methyl iodide are then added.

a After the solution has been allowed to stand for 4 days at room temperature methyl ethyl ketone is added to the point of incipient clouding and the solution left at room temperature for another 8 days. The finely crystalline precipitate is drawn oif, washed in methyl ethyl ketone, and dried in vacuo. 32.6 parts of hexamethylenebis-(N-methyl carbamic acid m-dimethylaminophenylester-iodomethylate) are obtained. The further addition of methyl ethyl ketone yields a little more of the substance which may be purified by dissolving for instance in absolute ethanol and subsequent precipitating with methyl ethyl ketone and appears as a white, finely crystalline, powder with a micro melting point between 138 and 139.5 C.

After quaternisation of the hexamethylene-bis-(N- methyl carbamic acid m-dimethylaminophenylester) with other alkylation reagents, such as an ethyl halogenide, an allyl halogenide, or a benzyl halogenide, the corresponding bis-quaternary compounds can be prepared. The iodides and bromides react readily and produce the quaternary compounds at room temperature. The chlorides often call for the application of heat to avoid long reaction times for quaternisation.

Example 2 ture for 4 hours. -The cooled product of the reaction is washed in water, a 5% solution of caustic soda, and again in water whereupon the xylene is removed by evaporation in vacuo. 26 parts of octamethyIene-bissQN methyl carbamic acid m-dimethylarninophenylester) are thereby obtained. p

10.9 parts of octamethylene-bis-(N-methyl carbamic acid m-dimethylaminophenylester) are dissolved in 40 parts of benzene and then boiled under reflux in the presence of animal charcoal for one hour. After filtration, the benzene is removed by distillation. The residue is dissolved in 100 parts of a methyl bromide solution in acetone containing 13 parts of methyl bromide and then allowed to stand. at room temperature for four days. The crystalline precipitate is drawnofi, washedin acetone, and dried in vacuo. In this manner 12.4 parts of octamethylene-bis-(N-methyl carbamic acid m-dimethylaminophenylester-bromomethylate). are obtained. The product precipitated from a solutio'n in acetic acid with methyl ethyl ketone is a white, finely crystalline, powder with a melting point between 150 and 154 C.

Example3 parts of N'.N.N'.N'-tetrarnethyl-hexamethylene-di amine are added dropwise to 100 parts 'of a solution of phosgene in toluene and the reagent mixture is.

kept at a temperature of 100 C. for 6 hours, the escaping unreacted phosgene being condensed and' repeatedly bubbled through the reagent mixture: again. After standing for 12 hours the mixture is; filtered and 60 parts of the clear toluene solution, removed by distillation. parts of ,B-dimethylaminoethanolare then added to the remaining solution of the hexarnethylene-bis-(N-methyl carbamic acid chloride) in toluene. When heated a precipitate appears. After standing for 12 hours at room temperature the deliquescent. crystals of the precipitate (hydrochloride of dimethylaminoetha-nol) are separated. The remaining toluene is removed bywarming the solution lightly in vacuo and in order to get rid of the excess of di-methylaminoethanol the residue'is left for one week in an open dish in vacuo over concentrated sulphuric acid. In this manner 21 parts of hexamethylene-bis-(N-methyl carbamic acid dimethylaminoethylester) are prepared in the form of a practically odourlessoil.

21 parts of this hexarne'thylene bis-(N-methyl carbamic acid dimethylaminoethylester) are dissolved in 125 parts of acetone and 40 parts of methyl iodide added. The reaction occurs when the solution is heated. Soon, fine white crystals appear which are drawn off after having been left to stand at room temperature for 12 hours, Washed in acetone and then dried. In this manner 35.3 parts of hexamethylene-bis-(N-methyl carbamic acid choline iodideester) are obtained which, after dissolving in methanol and subsequent precipitation with acetone have a micro melting point between 169 and 171 C.

Example 5 2 parts of sodium are dissolved in 24 parts of methanol and to the solution of sodium methylate formed 8.25 parts of 3-oxypyridine and. 90 parts of xylene (mixture of isomers) are added. Then the/mixture is distilled in an atmosphere of nitrogen as protecting gas until the boiling point of xylene is reached and the methanol is completely removed. The remainder is brought together with a solution of 11.7 parts of hexamethylene-bis-(N- methyl carbamic acid chloride) in 45' parts of xylene and maintained 4 hours at a temperature of C. under vigorous stirring.

After having been cooled it is washed three times in water, three times in a 5% solution of caustic soda, and then another three times in water. The solution in xylene is. dried. over sodium sulfate and the xylene is completely distilled oil in vacuo. Thus 11.0 parts of hexamethylenebis(N-n1ethyl carbamic acid-3-pyridyl ester) are ob tained.

6 parts of hexamethylene-bis-(N-methyl carbamic -acid- 3-pyridyl ester) are dissolved in 8 parts of acetone and the. solution is mixed with 10 parts of methyl iodide and left at room temperature. When the reaction is finished, the crystalline hexametlrylene-bis-(N-methyl carbamic acid-S-pyridyl ester-iodomethylate) precipitated is drawn off, washed acetone and dried. The raw product thus obtainedis.re-crystallisedin 24 parts of 96% ethanol. and yields 7.5 parts of hexamethylene-bis-(N-methyl. carbamic acid-3-pyridyl ester-iodomethylate) with a melting point of 152 to 157 C.

7.3 parts of hexamethylene-bis-(N-methyl carbamic acid S- yridyl ester) are dissolved in parts of acetone, then 22 parts of methyl bromide areadde'd and the mixture-is left to stand at room temperature until the reaction is finished, whereby crystals are precipitated. The reaction product after being drawn 0E and dried (9.9 parts) can be purified by dissolving in acetic acid and precipitating with methyl ethyl ketone. The hexamethylenebis-(N-methyl carbamic acid-3 pyridy1 ester bromomethylate) has a micro melting point between 147 and 150C.

Example 6 The substance is prepared in an analogous manner as described in the preceding example for hexamethylenebis-(N-methyl carbamic acid-S-pyridyl ester), by using decamethylene-bis-(N methyl carbamic acid chloride) instead of hexamethylene-bis-(N-methylcarbamic acid chloride). In this case there are obtained 10.1 parts of decamethylene-bis-(N-methyl carbamic acid-3-pyridyl ester) from 10 parts of decamethylene-bis-(N-methyl carbamic acid chloride).

13.1 parts of decamethylene-bis-(N-methyl carbamic acid-3-pyridyl ester) are dissolved in 8 parts of absolute ethanol and 200 parts of acetone, then 40 parts of methyl bromide are added to the solution and the mixture is left to stand at room temperature. After the end of the reaction the decamethylene-bi's-(N-methyl :carbamic acid- 3-pyridyl ester bromornethyl'ate) obtained in crystalline form is dissolved in absolute ethanol and precipitated with methyl ethyl ketone; thus 9.4 parts of the productwith a micro melting'point between 100 and 103 C. are obtained.

- Example 7 4.7 parts of hexamethylene-bis-(N-methyl carbamic acid m-dimethylaminophenylester) are dissolved in 40 parts of methyl ethyl ketone and to the solution 3.15 parts of dimethyl sulfate are added. After standing for several hours at room. temperature the hexamethylenebis-(N-methyl carbamic acid m-dimethylaminophenylester-methosulfate) is obtained in the form of a viscous oil.

Example-8 4.7 parts of hexarnethylene-bis-(N-methyl carbamic acid m-dimethylaminophenylester) are dissolved in 40 parts of methyl ethyl ketone and to the solution 6.3 parts of ethyl iodide are added. After standing for several days at a temperatureof 25 to 30 C. the hexamethylene-bis-(N-methyl carbamic acid m-dirnethyl-aminophenylester-iodoethylate) formed can be precipitated with precipitating agents convenient for such quaternary prodnote, as e. g. benzene.

Example 9 5.0 parts of odta'methYkne-bis-(N-methyl carbamic acid m-dimethyl-aminophenylester) are dissolved in 35 parts of methyl ethyl ketone. To this solution a solution of 3.8 parts of p-toluene sulfonic acid methylester in 20 parts of methyl ethyl ketone is added and the reaction mixture is maintained at a temperature of 60 C. for 9 hours. The octamethylene-bis-(N-methyl carbamic acid m-dimethyl-aminophenylester p-toluenesulfonate) is thrown out in the form of a viscous oil.

Equimolecular amounts of o-dialkyl aminophenols or p-dialkyl aminophenols or other m-dialkyl aminophenols respectively can be used instead of the m-dimethyl aminophenol applied according to the preceding examples, giving similar results. As examples for such dialkyl aminophenols m-diethyl aminophenol, m-dipropyl aminophenol, rn-diisobutyl aminophenol, m-di-n-butyl aminophenol, mmethyl ethyl aminophenol, and the corresponding or p-dialkyl aminophenols, further also di-cyclhexyl aminophenols, di-benzyl aminophenols and similar compounds may be mentioned.

Example Hexamethylene bis (N-methyl carbamic acid m-dimethyl-aminophenylester-bromomethylate) is obtained in the same manner as described in Examplel by quaternisation of hexamethylene-bis-(N-methyl carbamic acid m-dimethyl-aminophenylester) with methyl bromide instead of methyl iodide. After purification by dissolving in acetic acid and precipitating with methyl ethyl ketone the substance has a micro melting point of 170 to 173 C.

I claim:

1. A bis-quaternary salt of a carbamic acid ester of the formula Z.OOC.N.B.N.COO.Z

wherein Z is a tertiary amine radical selected from the group consisting of and A represents a radical selected from the group consisting of lower alkyl radicals with 1 to 3 carbon atoms, B represents a polymethylene radical with 2 to 10 carbon atoms, while R is a member selected from the group consisting of a lower alkyl radical with l to 3 carbon atoms, a cyclohexylradical and a benzylradical.

2. A bis-quaternary salt of a carbamic acid ester of the formula Z.OOO.N.B.N.COO.Z

wherein Z is a dimethylamino-phenylradical, A represents a radical selected from the group consisting of lower alkyl-radicals with l to 3 carbon atoms and B represents a polymethylene radical with 2 to 10 CI-Iz-groups.

3. A bis-quaternary salt of a carbamic acid ester of the formula Z.OOC.N.B.N.COOtZ wherein Z is a pyridylradical, A represents a radical se lected from the group consisting of lower alkyl-radicals with 1 to 3 carbon atoms and B represents a polymethylene radical with 2 to 10 CHz-groups.

4. A bis-quaternary salt of a carbarnic acid ester of the formula M-N N-( ah wherein n is an integer from 2 to 10.

5. A bis-quaternary salt of a carbamic acid ester of the formula OCO.N--(CH)1II.COO on; on: U

wherein n is an integer from 2 to 10.

6. A carbamic acid ester of the formula 2.0 O C.N.B.N.CO O.Z

wherein Z is a tertiary amine radical selected from the group consisting of and A represents a radical selected from the group consisting of lower alkyl radicals with l to 3 carbon atoms, B represents a polymethylene radical with 2 to 10 carbon atoms, while R is a member selected from the group consisting of a lower alkyl radical with 1 to 3 carbon atoms, a cyclohexylradical and a benzylradical.

7. A carbamic acid ester of the formula wherein Z is a dimethylamino-phenylradical, A represents a radical selected from the group consisting of lower alkylradicals with 1 to 3 carbon atoms and B represents a polymethylene radical with 2 to 10 CHz-groups.

8. A carbamic acid ester of the formula wherein Z is a pyridylradical, A represents a radical selected from the group consisting of lower alkylradicals with 1 to 3 carbon atoms and B represents a polymethylene radical with 2 to 10 CI-Ia-groups.

9. A carbamic acid ester of the formula wherein n is an integer from 2 to 10.

11. In a process of producing a bis-quaternary salt of a carbarnic acid ester of the general formula wherein Z is a tertiary amine radical selected from the group consisting of and A represents a radical selected from the group consisting of lower alkyl radicals with l to 3 carbon atoms, B represents a polymethylene radical with 2 to carbon atoms, while R is a member selected from the group consisting of lower alkyl radicals with 1 to 3 carbon atoms, a cyclohexylradical and a benzylradical, the step comprising reacting dicarbamic acid dichlorides of the general formula C1.CO.N.B.N.CO.C1

with a hydroxy compound of the formula ZOH, where Z corresponds to the above indicated designation, in an indifferent solvent, and then reacting the resulting bistertiary carbamic acid ester with a quaternizing agent of the formula RX wherein R corresponds to the above indicated designation and X is an anionic group, in an indifferent solvent and in an amount sufiicient to form said bis-quaternary carbamic acid ester compound.

12. In a process of producing a bis-quaternary salt of a carbamic acid ester of the general formula wherein Z is a tertiary amine radical selected from the group consisting of and A represents a radical selected from the group consisting of lower alkyl radicals with 1 to 3 carbon atoms, B represents a polymethylene radical with 2 to 10 carbon atoms, while R is a member selected from the group consisting of lower alkyl radicals with 1 to 3 carbon atoms, a cyclohexylradical and a benzylradical, the step comprising reacting dicarbamic acid dichlorides of the general formula 01.0 O.N.B.N.C 0.01

with a hydroxy compound of the formula [RZ.0HI*X- O.CO.N.(CH2)10.N.C 0.0

CH; CH:

said compound having a micro melting point of 103 C.

14. As a new product the octamethylene-bis-quaternary carbamic acid ester compound of the general formula said compound having a melting point of ISO-154 C.

15. As a new product the decamethylene-bis-quaternary carbamic acid ester compound of the general formula said compound having a micro melting point of 164- C.

16. As a new product the hexamethylene-bis-quaternary carbamic acid ester compound of the general formula said compound having a micro melting point of 170173' C.

17. As a new product the hexamethylene-bis-quaternary carbamic acid ester compound of the general formula O.CO.N.(CH2)a.N.C 0.0 G

CH: C

said compound having a micro melting point of 147- 150 C.

References Cited in the file of this patent UNITED STATES PATENTS Aeschlimann July 16, 1940 OTHER REFERENCES Herring et al.: Journal of Pharmacology and Experimental Therapeutics, vol. 103, p. 347 (1951).

Kraup et al.: Nauyn-Schmiedebergs Archiv., Fur Experimentelle Pathologie und Pharmakologie Bd 122, pp. -182 (1954). 

1. A BIS-QUATERNARY SALT OF A CARBAMIC ACID ESTER OF THE FORMULA 